Collagen is the most ubiquitous structural protein and an essential building block in extracellular matrix of connective tissue. Mechanical loading is an important factor responsible for collagen-related injuries and diseases such as osteoarthritis, excessive joint laxity, poor ligament healing, tendon adhesions and enthesitis. Our current understanding of how the mechanical factors influence collagen and its pathological conditions is based on gross-level biomechanics, or information averaged over millions of collagen and other molecular structures. The mechanical characteristics of collagen at the molecular level, where disorders originate, are largely undefined. The proposed research will initiate an innovative investigation on the biomechanics of collagen molecules. The long-term objectives are to provide a molecular biomechanical basis of collagen functions and properties for in-depth understanding of the pathological mechanisms in collagen-related disorders and for the development of new therapeutic interventions. In our pilot studies, we have developed a biomechanical testing system - a state-of-the-art optical tweezers/interferometer - that is capable of measuring the mechanical properties of single collagen molecules. A goal of this investigation will be to quantify the mechanical properties of the most common and important fibril-forming collagen molecules in ligament, tendon and bone (type I)- and in cartilage (type II). A second goal will be to determine the effects of selected collagen abnormalities on the mechanical properties of molecules. Two recombinant models of collagen mutations, one with a large deletion in gene and the other found in inherited osteoarthritis, will be used. It is anticipated that the results of these findings will demonstrate for the first time the intrinsic differences in mechanical properties among different types of collagen, as well as collagen mutations, and therefore, new insight into the mechanical role in collagen ultrastructure. The ability to measure biomechanical alterations in the molecule itself may also permit detection of molecular abnormalities and gene mutations before they are clinically evident.